DESCRIPTION: The principal investigator notes that synthetic organic chemistry continues to play a dominant role in optimizing the therapeutic-activity of biologically active structures. He states that research in his group is directed toward the development of novel catalytic transition-metal-mediated carbon-carbon bond forming reactions applied to the carbocyclization of unsaturated substrates. The goal is to provide novel cyclization methodologies for organic synthesis that utilize common organic functional groups and proceed catalytic in metal. The principal investigator notes that to date his approach has been to address both mechanistic aspects of the cyclizations as well as very simple synthetic applications of the new methods. He indicates that on the basis of the discovery and developmental work that was completed under prior NIH support there is a good survey of the accessible rings systems, functionalities tolerated and the stereochemical control in both the iron-catalyzed triene (enediene) carbocyclizations and the palladium-catalyzed tetraene (bis-diene) carbocyclizations. He now is to focus more targeted problems in the synthesis of pharmaceutically relevant molecules. It is indicated that the specific aim of the proposal is to demonstrate the viability of these novel bond constructions as strategy-level reactions for complex molecule total synthesis. The targets are to include tetronasin, prostanoids, brefeldin, yohimbine and steroids. It is noted that these targets have not been previously synthesized via metal-mediated carbocyclization approaches. The principal investigator indicates that their syntheses are designed to exploit the unique structure and reactivity of organometal intermediates to control the stereochemical and regiochemical course of carbon-carbon bond construction and notes that each application is designed to push the limits of the metal-mediated cyclization methodology, and as such requires targeted developmental work to be successful.